The U.S. Food and Drug Administration announced Friday it is investigating serious adverse events, including one death, in patients treated with Takeda Pharmaceuticals' enzyme replacement therapy Adzynma for congenital thrombotic thrombocytopenic purpura (cTTP).
The reported fatality occurred in a pediatric cTTP patient who developed progressive neurological symptoms approximately 10 months after starting prophylactic treatment with Adzynma. The FDA stated the death "appears to be related to Adzynma" and noted the patient was found to be producing neutralizing antibodies against ADAMTS13, the enzyme that Adzynma is designed to replace.
Antibody Development Raises Safety Concerns
The FDA received multiple reports of patients developing neutralizing antibodies against ADAMTS13 following Adzynma treatment. These antibodies can interfere with the drug's therapeutic effect and potentially cause serious complications in cTTP patients who rely on functional ADAMTS13 enzyme for proper blood clotting regulation.
The pediatric patient who died had previously experienced severe allergic reactions to fresh frozen plasma, a standard treatment for cTTP that can also replace the mutated enzyme. This medical history led the FDA to believe the antibody reaction is specifically related to enzyme replacement therapy with Adzynma rather than other treatment factors.
Diagnostic Limitations Complicate Investigation
A significant challenge in the investigation is that current laboratory assays cannot differentiate between antibodies produced against Adzynma's recombinant ADAMTS13 and antibodies directed against the patient's own endogenous ADAMTS13 protein. This diagnostic limitation makes it difficult to determine the exact mechanism behind the adverse reactions.
The FDA emphasized that these antibody-related adverse events occurred in post-marketing settings and were not observed during Adzynma's clinical trials. While the drug's current labeling includes information about the potential risk of developing neutralizing antibodies, it does not specifically address postmarketing reports of such reactions.
Understanding Congenital TTP
Congenital thrombotic thrombocytopenic purpura is a rare blood-clotting disorder affecting fewer than 1 in 1,000 people. The condition results from mutations in the ADAMTS13 protein, which plays a crucial role in the body's clotting cascade. Patients with cTTP develop blood clots in small vessels throughout their body, with symptoms typically manifesting during infancy or early childhood.
Adzynma contains two copies of the human ADAMTS13 protein and is indicated for both prophylactic and on-demand enzyme replacement therapy in cTTP patients. The treatment aims to restore normal blood clotting function in patients whose genetic mutations prevent them from producing functional ADAMTS13 enzyme.
Regulatory Response and Next Steps
The FDA is conducting a comprehensive investigation into the risk of developing neutralizing antibodies with serious or fatal outcomes following Adzynma treatment. The agency stated it will evaluate the need for further regulatory action based on its findings.
This investigation highlights the ongoing challenges in treating rare genetic disorders, where limited patient populations during clinical trials may not reveal all potential safety signals that emerge during broader clinical use.
